Du Kuo, Williams C David, McGill Mitchell R, Jaeschke Hartmut
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Toxicol Appl Pharmacol. 2014 Nov 15;281(1):58-66. doi: 10.1016/j.taap.2014.09.002. Epub 2014 Sep 16.
Acetaminophen (APAP) overdose causes severe hepatotoxicity in animals and humans. However, the mechanisms underlying the gender differences in susceptibility to APAP overdose in mice have not been clarified. In our study, APAP (300mg/kg) caused severe liver injury in male mice but 69-77% lower injury in females. No gender difference in metabolic activation of APAP was found. Hepatic glutathione (GSH) was rapidly depleted in both genders, while GSH recovery in female mice was 2.6 fold higher in the mitochondria at 4h, and 2.5 and 3.3 fold higher in the total liver at 4h and 6h, respectively. This faster recovery of GSH, which correlated with greater induction of glutamate-cysteine ligase, attenuated mitochondrial oxidative stress in female mice, as suggested by a lower GSSG/GSH ratio at 6h (3.8% in males vs. 1.4% in females) and minimal centrilobular nitrotyrosine staining. While c-jun N-terminal kinase (JNK) activation was similar at 2 and 4h post-APAP, it was 3.1 fold lower at 6h in female mice. However, female mice were still protected by the JNK inhibitor SP600125. 17β-Estradiol pretreatment moderately decreased liver injury and oxidative stress in male mice without affecting GSH recovery.
The lower susceptibility of female mice is achieved by the improved detoxification of reactive oxygen due to accelerated recovery of mitochondrial GSH levels, which attenuates late JNK activation and liver injury. However, even the reduced injury in female mice was still dependent on JNK. While 17β-estradiol partially protects male mice, it does not affect hepatic GSH recovery.
对乙酰氨基酚（APAP）过量在动物和人类中会导致严重的肝毒性。然而，小鼠对APAP过量易感性的性别差异背后的机制尚未阐明。在我们的研究中，APAP（300mg/kg）在雄性小鼠中引起严重肝损伤，但在雌性小鼠中损伤低69 - 77%。未发现APAP代谢活化存在性别差异。两性肝脏中的谷胱甘肽（GSH）均迅速耗竭，而雌性小鼠线粒体中GSH在4小时时的恢复速度快2.6倍，在全肝中4小时和6小时时分别快2.5倍和3.3倍。GSH的这种更快恢复与谷氨酸 - 半胱氨酸连接酶的更大诱导相关，减轻了雌性小鼠的线粒体氧化应激，6小时时较低的GSSG/GSH比值（雄性为3.8%，雌性为1.4%）以及最小的小叶中央硝基酪氨酸染色表明了这一点。虽然在APAP给药后2小时和4小时时c - jun氨基末端激酶（JNK）活化相似，但在6小时时雌性小鼠中的活化水平低3.1倍。然而，雌性小鼠仍受到JNK抑制剂SP600125的保护。17β - 雌二醇预处理适度降低了雄性小鼠的肝损伤和氧化应激，而不影响GSH恢复。
雌性小鼠较低的易感性是通过线粒体GSH水平加速恢复从而改善活性氧解毒实现的，这减轻了晚期JNK活化和肝损伤。然而，即使雌性小鼠损伤减轻仍依赖于JNK。虽然17β - 雌二醇部分保护雄性小鼠，但不影响肝脏GSH恢复。
